The human inherited disorders of sphingolipid metabolism (Gaucher, Krabbe, Farber, Niemann-Pick, etc.) are the result of deficient lipid hydrolases. In the infantile forms, the patients exhibit severe mental retardation, neurological degeneration, and major organ involvement. A wide variety of distressing symptoms can appear. Research on these disorders has been hampered by the lack of small animals bearing the same genetic disorders. We hope to produce model versions of the disorders by devising inhibitors of the specific hydrolytic enzymes and injecting them into young mice or rats. The resulting progressive changes in the animals will be followed by chemical assays, measurement of incorporated isotopic precursors, and morphological examination. It is expected that we will be able to clarify the causal relations between the primary defect and the many metabolic changes that result. The model animals might be useful for the determination of optimal ways of administering normal, corrective enzymes (enzyme supplementation). Other drugs will be synthesized in an effort to produce inhibitors of the enzymes that make the accumulating sphingolipids. It is possible that they would alleviate the symptoms produced in the above model animals, since the rate of accumulation should be slowed. It is hoped that the new drugs would have low toxicity in the intact animals and thus offer promise in the treatment of patients with sphingolipid genetic diseases.